Antiresorptive agents, such as bisphosphonates (BPs) and Denosumab, are used to manage bone malignancy and metabolic bone diseases. Antiresorptive related osteonecrosis of the jaws (ONJ), a serious complication, particularly of the most potent regimens, presents as clinically exposed bone in the maxillofacial region for more than 8 weeks, and is associated with severe pain, swelling, infection, fistulae, and jaw fracture. ONJ pathophysiology remains largely elusive. ONJ presence under medications with distinct pharmacologic actions strongly points to osteoclast inhibition as central in disease pathogenesis. A puzzling, unanswered, question is ONJ's predilection for the jaws. ONJ is most commonly associated with tooth extraction in patients receiving high dose antiresorptives. However, in adults, teeth are extracted mainly due to severe periodontal disease or extensive caries that cause pulpal necrosis and periapical disease. Furthermore, several ONJ patients present without history of tooth extraction. From studies supported by this grant, we have reported the importance of dental disease for the establishment of ONJ in rats and mice. Interestingly, in both animal models, histologically necrotic bone is present. However, bone exposure, consistent with clinical ONJ, is seen in only 33% of the animals with osteonecrosis, suggesting that bone exposure is not prerequisite for bone necrosis. Equipped with these models, we have established qualitative and quantitative measures that mimic patient ONJ and evaluate disease burden. Preliminary data, presented herein, indicate that osteonecrotic changes occur as early as two weeks, while extraction of diseased teeth leads to incomplete soft tissue healing and bone exposure. Pharmacologic treatments alleviate ONJ severity, providing possible interventional tactics with clinical implications. Osteoblast lineage experiments demonstrate expansion of osteoblast precursors in the alveolar bone of BP treated mice with dental disease. Importantly, inflammation and BP treatment induce osteonecrosis in calvariae and femurs of mice, suggesting that, given the right conditions, other bones are subject to BP-associated osteonecrosis. Our objective is to characterize pathophysiologic mechanisms of ONJ and explore potential interventional approaches to ameliorate disease severity. We hypothesize that severe dental disease plays a central role in antiresorptive induced ONJ. We propose: 1. To study early responses in ONJ development, and elucidate the effect of BP withdrawal and diseased tooth extractions in ONJ progression, 2. To explore cyclooxygenase (COX) pathway involvement in ONJ pathophysiology, and 3. To study the effects of BPs and inflammation on calvariae and femoral defect healing.